Premium
Akt2, but not Akt1 or Akt3 mediates pressure‐stimulated serum‐opsonized latex bead phagocytosis through activating mTOR and p70 S6 kinase
Author(s) -
Shiratsuchi Hiroe,
Basson Marc D.
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21295
Subject(s) - phagocytosis , protein kinase b , pi3k/akt/mtor pathway , ly294002 , microbiology and biotechnology , akt1 , biology , chemistry , phosphorylation , signal transduction
Monocytes and macrophages play critical roles in innate host defense and are sensitive to mechanical stimuli. Tissue pressure is often altered in association with inflammation or infection. Low pressure (20 mmHg), equivalent to normal tissue pressure, increases phagocytosis by primary monocytes and PMA‐differentiated THP‐1 macrophages, in part by FAK and ERK inhibition and p38 activation. PI‐3K is required for macrophage phagocytosis, but whether PI‐3K mediates pressure‐stimulated phagocytosis is not known. Furthermore, little is known about the role played by the PI‐3K downstream Kinases, Akt, and p70 S6 kinase (p70S6K) in modulating macrophage phagocytosis. Thus, we studied the contribution of PI‐3K, Akt, and p70S6K to pressure‐increased serum‐opsonized bead phagocytosis. Pressure‐induced p85 PI‐3K translocation from cytosolic to membrane fractions and increased Akt activation by 36.1 ± 12.0% in THP‐1 macrophages. LY294002 or Akt inhibitor IV abrogated pressure‐stimulated but not basal phagocytosis. Basal Akt activation was inhibited 90% by LY294002 and 70% by Akt inhibitor IV. Each inhibitor prevented Akt activation by pressure. SiRNA targeted to Akt1, Akt2, or Akt3 reduced Akt1, Akt2, and Akt3 expression by 50%, 45%, and 40%, respectively. However, only Akt2SiRNA abrogated the pressure‐stimulated phagocytosis without affecting basal. Pressure also activated mTOR and p70S6K. mTORSiRNA and p70S6K inhibition by rapamycin or p70S6KSiRNA blocked pressure‐induced, but not basal, phagocytosis. Changes in tissue pressure during inflammation may regulate macrophage phagocytosis by activation of PI‐3K, which activates Akt2, mTOR, and p70S6K. J. Cell. Biochem. 102: 353–367, 2007. © 2007 Wiley‐Liss, Inc.